| First Author | Liu L | Year | 2020 |
| Journal | J Clin Invest | Volume | 130 |
| Issue | 9 | Pages | 4710-4725 |
| PubMed ID | 32544095 | Mgi Jnum | J:299499 |
| Mgi Id | MGI:6491493 | Doi | 10.1172/JCI136155 |
| Citation | Liu L, et al. (2020) Histone methyltransferase MLL4 controls myofiber identity and muscle performance through MEF2 interaction. J Clin Invest 130(9):4710-4725 |
| abstractText | Skeletal muscle depends on the precise orchestration of contractile and metabolic gene expression programs to direct fiber-type specification and to ensure muscle performance. Exactly how such fiber type-specific patterns of gene expression are established and maintained remains unclear, however. Here, we demonstrate that histone monomethyl transferase MLL4 (KMT2D), an enhancer regulator enriched in slow myofibers, plays a critical role in controlling muscle fiber identity as well as muscle performance. Skeletal muscle-specific ablation of MLL4 in mice resulted in downregulation of the slow oxidative myofiber gene program, decreased numbers of type I myofibers, and diminished mitochondrial respiration, which caused reductions in muscle fatty acid utilization and endurance capacity during exercise. Genome-wide ChIP-Seq and mRNA-Seq analyses revealed that MLL4 directly binds to enhancers and functions as a coactivator of the myocyte enhancer factor 2 (MEF2) to activate transcription of slow oxidative myofiber genes. Importantly, we also found that the MLL4 regulatory circuit is associated with muscle fiber-type remodeling in humans. Thus, our results uncover a pivotal role for MLL4 in specifying structural and metabolic identities of myofibers that govern muscle performance. These findings provide therapeutic opportunities for enhancing muscle fitness to combat a variety of metabolic and muscular diseases. |
